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CLINICAL STUDY: HEART FAILURE

Apoptotic pathway activation from mitochondria and death receptors without caspase-3 cleavage in failing human myocardium

Fragile balance of myocyte survival?

Robert J. Scheubel, MD^*,*, Babett Bartling, MS^*, Andreas Simm, PhD^*, Rolf-Edgar Silber, MD^*, Kostas Drogaris, MS, Dorothea Darmer, PhD and Juergen Holtz, MD

^* Clinic for Cardiothoracic Surgery, Martin Luther University Halle-Wittenberg, Halle/Saale, Germany
Institute of Pathophysiology, Martin Luther University Halle-Wittenberg, Halle/Saale, Germany

Manuscript received July 12, 2001; revised manuscript received October 4, 2001, accepted November 1, 2001.

^* Reprint requests and correspondence: Dr. Robert J. Scheubel, Klinik für Herz- und Thoraxchirurgie, Martin-Luther-Universität Halle-Wittenberg, Ernst-Grube-Str. 40, D-06097 Halle/Saale, Germany.
robert.scheubel{at}medizin.uni-halle.de

OBJECTIVES: Activation of the caspase cascade through the mitochondrial and/or death receptor pathway was investigated in the failing human myocardium, in which the mode and extent of the cascade activation are unknown.

BACKGROUND: In terminal heart failure, a loss of cardiomyocytes by overload-induced apoptosis is an attractive mechanism, explaining the progressive character of the disease. However, its relevance is unclear, because the specificity of probes for apoptotic deoxyribonucleic acid damage is under debate.

METHODS: Left ventricular specimens from 36 explanted failing and 21 nonfailing donor hearts were used for messenger ribonucleic acid detection by semiquantitative reverse-transcription polymerase chain reaction. From these groups, immunoblot analysis was performed in samples from nine failing and six nonfailing donor hearts.

RESULTS: In terminally failing hearts, there was a significant accumulation of cytochrome c in the cytosol, which was associated with activation of caspase-9 and downregulation of its inhibitor, caspase-9S. Similarly, the death receptor-induced pathway revealed activation of caspase-8, combined with downregulation of its inhibitors, flice-like inhibitory protein-L (FLIP_L) and FLIP_S. The unspecific caspase inhibitors, XIAP, hIAP-1 and hIAP-2, were also downregulated. However, the terminal effector caspase-3 was not activated, and its substrate gelsolin, acting in its uncleaved form as a feedback inhibitor of caspase-3, was not cleaved.

CONCLUSIONS: In the terminally failing human myocardium, the caspase cascade is partially activated in the presence of a consistent phenotype shift toward enhanced susceptibility to apoptosis. Although the system is still under a fragile control, the partial initiation of the apoptotic program may be of functional relevance also for the surviving cardiomyocytes.

Abbreviations and Acronyms   TUNEL   AIF   apoptosis-inducing factor   ANP   atrial natriuretic peptide   ATP   adenosine triphosphate   CAD   coronary artery disease   DCM   dilated cardiomyopathy   DNA   deoxyribonucleic acid   FLIP   flice-like inhibitory protein   hIAP   human inhibitor of apoptosis protein   HRP   horseradish peroxidase   IAP   inhibitor of apoptosis protein   IgG   immunoglobulin G   mc   monoclonal   mRNA   messenger ribonucleic acid   RNA   ribonucleic acid   RT-PCR   reverse-transcription polymerase chain reaction   pc   polyclonal   TNF   tumor necrosis factor   TUNEL   terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling   VAD   ventricular assist device   XIAP   X-linked inhibitor of apoptosis protein

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